Off-label use of medications is a major concern for the United States Food and Drug Administration, which approves drugs predominantly based on their intended use. When drugs are used “off-label,” i.e. for indications not approved by the Food and Drug Administration, they are being used in treatments that have not undergone rigorous FDA review for safety and efficacy in the off-label indication. In recent years, FDA has become increasingly cognizant of the potential for such off-label uses, especially in acute pain medications which, while nominally approved for acute pain, have tremendous potential for abuse in the chronic pain market where long-term safety issues are paramount. To overcome its concerns, FDA has informally required applicants to study safety in such off-label uses before approving many drugs for their requested indications. These regulatory demands increase the cost of drug development tremendously, and discourage innovation for new drugs and clinical indications.
The bioavailability of pharmaceutical products is a critical concern in the design of acute pain medications. The pharmacokinetics of a drug, which measure the time it takes a drug to become bioavailable and its concentration profile in serum over time, can have a significant effect on the effectiveness of a drug, as well as its safety. Pharmacokinetics are of particular concern for drugs that require an immediate onset of action, such as drugs used in the treatment of acute pain.
Various factors can influence the time it takes for a drug to become bioavailable in therapeutically effective concentrations. For orally administered solid dosage forms, some of the most important parameters include the disintegration/dissolution time of the drug, the stability and solubility of the molecule in the gastrointestinal tract, and first pass metabolism, to mention just a few. For some drugs such as potassium diclofenac the pH of the formulation can also affect its bioavailability. For example, it is known that diclofenac potassium has a tendency to precipitate in an acidic environment, thereby making it less bioavailable. This problem is highlighted in bioavailability studies of Cataflam, a commercially marketed form of diclofenac potassium, which exhibits two concentration peaks in the bloodstream when orally ingested.
When rapid bioavailability is desired, preferred modes of administration include parenteral, inhalation, mucosal and buccal administration. Tablets and capsules are generally available only in immediate release, extended release, and delayed release formats, and are not typically employed when rapid bioavailability is desired because of the time it takes for the dosage form to dissolve, and the resulting delay in gastrointestinal absorption. A novel delivery system for orally delivering diclofenac in a rapidly bioavailable tablet has been proposed in PCT/EP97/02709 (published as WO 97/44023), but solid oral dosage forms based on this type of platform are clearly the exception and not the rule.
The use of blister packs to package pills has become increasingly popular among specialty dosage forms such as orally disintegrating tablets, and drugs that are administered according to a predetermined schedule, such a birth control pills. In addition, the inventors are aware of one diclofenac potassium tablet formulated for rapid bioavailability that is marketed in Europe and packaged in a conventional blister pack. Generally, a conventional blister card package provides a container for individual dosages of the medicament separately packaged for delivery of the individual dosage to a patient. Typically, a blister card package contains a number (usually about 6-8) of individual dosages on a card where each dosage is separately contained and can be separated by perforations such that it can be readily detached. The blister card package is usually constructed of several layers. The top layer is a container sheet or container formstock constructed of a rigid material having integrally formed cavities or wells designed to hold the dosage form. The container sheet is sealed to a closure sheet (or lidstock) generally constructed of a foil and paper laminate. The blister package can be designed for removal of the dosage form from the container in a variety of ways. In some packages, the dosage is removed by pressing it through the closure sheet, where the closure sheet is made from a rupturable material. In other designs, the closure sheet is designed to be peeled off from the container sheet to remove the dosage form. Alternatively, the blister is scored to form a weakened area enabling the user to tear the blister and expose the cavity containing the tablet.